Sleeping is a physiological process which is controlled by two biological processes, the homeostatic mechanism and the circadian rhythm. Most adults need about eight hours average of sleeping each night, on a regular basis, in order to feel rested and alert during the daytime. Any change in this routine disrupts the delicate balance between two processes that interact to regulate sleeping. The homeostatic mechanism manifests itself as a growing impulse towards sleeping that accumulates through the alert period, typically during the daytime, and fades away through the sleeping period. The circadian rhythm operates as a 24-hour internal clock; as a part of this cyclic process, the body releases hormones, such as melatonin, in order to help the individual know when is the right time to sleep and to wake. The sleeping-wakefulness circadian rhythm shows a biphasic curve with the greater impulse toward sleeping occurring between midnight and 5 A.M., and between 2 and 4 in the afternoon.
Many physiological functions are characterized by daytime rhythms, in which circulating hormone levels fluctuate during the daytime and/or nighttime. Certain clinical disorders, such as insomnia, are associated with abnormalities in these rhythms. The time of administration, within 24-hour periods, of drugs intended for prevention and treatment of such disorders may be a critical factor in the determination of the efficacy of therapy.
Insomnia is one of the most prevalent sleeping diseases and refers to a clinical condition, which lasts at least one month, of difficulties in conceiving sleeping, or keeping the sleeping state, of waking frequently during nighttime or very early in the morning or also to an unsuitable perception of sleeping. This precludes the recovery that the body needs during the nighttime rest, the possible consequences being daytime somnolence, low concentration, tiredness and disability to feel active during the day.
A study by the National Sleep Foundation of the United States in 2002 reported that 74% of American adults experiment problems in sleeping several nights a week or more, 39% sleep less than seven hours per night and 37% exhibit somnolence during the daytime, thus interfering with their daily activities.
In anxiety states the presence of associated insomnia is frequent. Specialists think that the prevalence of insomnia is also related to age and gender of individuals, the prevalence being higher in older individuals, especially adults older than 65, being women the most affected.
Primary insomnia is sleeplessness that is not attributable to a medical, psychiatric, or environmental cause.
In the United States, primary insomnia is diagnosed in approximately 15% of patients with insomnia who are referred to sleep disorder centers following exclusion of other predisposing conditions. Primary insomnia is estimated to occur in 25% of all patients with chronic insomnia.
Despite that the consequences associated with chronic insomnia remain debatable, the following associations have been noted:                increased risk of mortality is associated with short sleep lengths;        insomnia is the best predictor of the future development of depression;        catastrophic worry about the consequences of not sleeping is common among patients with chronic insomnia and serves to maintain the sleep disturbance;        increased risk exists of developing anxiety, alcohol and drug use disorders, and nicotine dependence;        poor health and decreased activity occur;        
The ideal hypnotic or hypnophore is a drug that will induce sleeping in a quick, predictable fashion. It shall keep sleeping for a 7 to 8-hour period and avoid frequent awakenings. It must preserve sleep architecture with all its stages and must not induce adverse effects such as hang over (resaca matinal, in Spanish).
Early treatments for insomnia usually used central nervous system (CNS) depressants such as barbiturates. These compounds have shown a series of drawbacks. Due to their long half-life, they are typically long-acting (around 8-50 hours) and exhibit a largely known spectrum of side effects, including drowsiness, confusion, depression effects, and the next day hang over. Additionally, the chronic and wrong use of these compounds, i.e. without medical monitoring, has lead to physical and psychological dependence in some cases.
During the '80s, the pharmacological treatment of insomnia abruptly changed from barbiturates and other CNS depressants to the class of benzodiazepines of sedative-hypnotic effect. This kind of compounds produces a soothing effect, resulting in a state similar to sleeping in human beings and animals, with a greater safety range than previously used hypnotics. However, many benzodiazepines have side effects which limit their usefulness in certain populations of patients.
These problems include synergism with other CNS depressants (especially alcohol), development of tolerance with dose repetition, dependence, withdrawal, insomnia rebounding after dosing discontinuation, the effects of hang over the next day and weakening of psycho-motor functioning and memory. Somnolence on the next day and weakening of memory, which may include amnesia of events that occurred either before or after drug administration, are of special concern in elderly people, whose cognitive functions may already be damaged by the aging process.
In spite of the above, benzodiazepines have still been used for many decades and have become increasingly popular due to their low toxicity as compared to other drugs of similar action.
Diseases treated with benzodiazepines are a wide range of pathologies since they have several effects. The best known effects of benzodiazepines are as anticonvulsants, antipsychotic, muscle relaxants, sedatives and hypnotics. When benzodiazepines are used, some of their effects are desired with respect to the specific disorder treated, but others are considered side effects. Even at the dose levels used, for example against insomnia, the sedative effect of benzodiazepines may be a great disadvantage. Therefore, it is advantageous and important to find a form of administration of benzodiazepines which allows for application of the right and necessary dose to achieve the desired affect and which allows for better compliance of the patient. Some drugs which are only available as oral tablets or pills may be difficult to administer to elderly people and children, and hence it is of practical importance the availability of a pharmaceutical unit dosage form which disintegrates in a few seconds and whose active principle is absorbed through the sublingual and buccal mucosa of the patient.
Therefore, there is still a need to find a form of administration of benzodiazepines that is efficient and with a quick action onset in the treatment of primary insomnia or associated to anxiety states.
Alprazolam (28981-97-7) is a short-acting benzodiazepine described during 1970 in patents DE 2.012.190 (Sep. 24, 1970) and U.S. Pat. No. 3,987,052 (Oct. 19, 1976), which has demonstrated an interesting anxiolytic activity. However, it has not yet been approved for use in the short-term treatment of insomnia, neither in the United States nor in Europe.
Throughout the years, the search for new pharmaceutical forms containing alprazolam or new routes of administration different from the traditional pharmaceutical form (oral tablets) has been a subject of interest. Generally in order to reach the presence of alprazolam in blood in as little time as possible since the administration to the patient, thus assuring the quick start of the therapeutic effect.
Literature indicates that when the active ingredient is absorbed through the sublingual and buccal mucosas, such absorption allows for a rapid bioavailability thereof as the active ingredient directly enters the circulatory system, thus avoiding the gastrointestinal passage and the subsequent liver passage (S. Bredenberg et al (European Journal of Pharmaceutical Sciences 20 (2003) 327-334). Thus, in the recent years the patent literature mentions, among others, the following formulations.
Dugger III Harry et al. in US Patent Application 2004/0141923 AI (Jul. 22, 2004)) disclose a spray for buccal use containing alprazolam.
Although said document claims and describes generally a method for inducing sleep comprising spraying the oral mucosa of the patient with a “therapeutically effective amount” of the buccal spray containing alprazolam of the invention, it can be considered that such a statement is a mere expression of wish, because it lacks a technical basis. As a matter of fact, said document is totally silent as concerns the “application as a sleeping inductor” of alprazolam, there is no specific test supporting such a statement and, consequently, it is silent as concerns how much a “therapeutically effective amount” means in said treatment, there is no disclosure about the dosing in the treatment of insomnia. Moreover, in the specification alprazolam is described as being utilized for the treatment of anxiety and associated symptoms such as depression, dysthymic disorders such as “neurotic chronic” depression, panic attacks, agoraphobia and other phobias, obsessive-compulsive disorders, personality disorders.
Rabinowitz et al. (U.S. Pat. No. 6,737,048 B2 (May 18, 2004) and U.S. Pat. No. 7,060,255 B2 (Jun. 13, 2006)) disclose therapeutic forms containing alprazolam, among other benzodiazepines, for its administration by inhalation. However, both patents are not only silent as concerns suitable use and doses of alprazolam for the treatment of insomnia but rather advise the use thereof in situations wherein a sustained action of the medicament is desired, such as for example in panic attacks.
Los Mario in Mexican Patent MX 231185 (Oct. 10, 2005) and Argentine Patent Application (P000102422) published under number AR 32.585 (Nov. 19, 2003); discloses a procedure to prepare sublingual tablets containing alprazolam; useful for the treatment of panic attacks or acute anxiety episodes. This document is also silent as concerns the use of sublingual tablets as sleep inductors in primary insomnia or insomnia associated to anxiety states. In addition, at commercial scale, the procedure described therein has presented frequent practical problems of agglomeration during granulation.
Therefore, there still exists the need to provide a method for the treatment of insomnia comprising the administration of a benzodiazepine, preferably alprazolam; not having remarkably the side effects of benzodiazepines; in a suitable pharmaceutical form of easy disintegration and absorption which allows for quick start of action, and with a dosage and daily posology which allows the patient to comply the indicated treatment better.